Stress-related disorders such as major depressive disorder are serious mental illnesses that affect over 20 million Americans. Endocannabinoids, analogs of A9-THC, are neuromodulators implicated in regulating stress and anxiety. The long-term objective of this proposal is to determine the function of the endocannabinoid system in the etiology and pathophysiology of mood disorders. The specific hypothesis is that chronic mild stress, an animal model of depression, differentially regulates CB1 receptor levels in a gender-specific manner in rats and that this difference underlies the higher vulnerability of females to depressive disorders. This hypothesis is based on the following observations: 1) Depressive disorders are twice as prevalent in women than men 2) Chronic mild stress downregulates the cannabinoid receptor, CB1, in male rats, 3) Disruption of CB1 receptor increases behavioral responses to stress and anxiety, and 4) Disrupting CB1 receptors also enhances the acquisition and impairs extinction to acquired to fear. The three specific aims to be tested are: 1) To determine if chronic mild stress differentially regulates CB1 receptor levels in the hippocampus of male and female rats. 2) To determine if chronic mild stress modulates responses to hippocampal-dependent fear conditioning. 3) To determine if the chronic mild stress modulation of fear conditioning is CB1 receptor dependent. Hippocampal CB1 receptor levels will be assessed using Western immunoblotting following three-weeks of a chronic mild stress protocol. Fear conditioning will be performed with established classical-conditioning protocols. [unreadable] [unreadable]